Peripheral artery disease (PAD) is a major complication of atherosclerosis that affects >8 million people in the United States alone. Intermittent claudication (IC), defined as leg pain with walking that is relieved with rest, is the most frequent clinical manifestation of PAD. The number of patients with, and the health care costs of, PAD will increase as the prevalence of PAD is associated with advancing age, diabetes, and smoking. Our application will test the reuse of zibotentan (ZD4054), an orally active, endothelin type A antagonist in patients with IC. The study will seek to confirm the safety and tolerability of 10mg of ZD4054 in patients with intermittent claudication (Rutherford II or III and, in parallel, establish the capacity of ZD4054 to change calf muscle perfusion, as assessed by contrast-enhanced magnetic resonance imaging, functional treadmill performance, and quality of life indicators. The study will be a 1:1 randomized, double-blind, placebo-controlled trial of 44 subjects with intermittent claudication with randomization stratified based on the entr calf muscle perfusion. We will use magnetic resonance imaging to quantify changes in blood flow to the ischemic limb over time and compare drug to placebo. Based on the prior experience and the known tolerability of ZD4054, the experience of the investigative team with a mechanistically appropriate end-point measure that is part of other NIH funded projects, we will be proceed directly to this Phase II trial. The primary endpoint of the study will be the change in absolute perfusion in the index calf muscle from baseline to follow-up, after 12 weeks on the 10 mg dose or placebo. Additional outcome measures will be: a) ability of patients with PAD to tolerate 10 mg dose of ZD4054 vs. placebo; b) freedom from unexpected serious adverse events; c) change in peak walking time from baseline to 12 weeks between 10 mg of ZD4054 and placebo groups; d) change in ABI from baseline to 12 weeks between 10 mg of ZD4054 and placebo groups, and; d) change in quality of life measure between 10 mg of ZD4054 and placebo groups.